Project Summary/Abstract The incidence of Acute Pancreatitis (AP) in children has been rising to 1/10,000 cases. Diabetes mellitus (DM) can result from AP in a subset of patients, and that leads to increased morbidity especially if underdiagnosed, given that there is no current method for DM screening post AP in the pediatric population. Post AP DM remains understudied with outcomes poorly defined. Previous studies in DM post AP are mostly single-centered and retrospective in nature, and thereby insufficient for understanding the natural history. From our previous work we have found up to 30% of children develop pre-DM or DM post AP and that a subset of patients have islet auto antibodies (Ab) positive testing post AP but that does not always translate to a full diagnosis of DM. This begs the question whether these Ab influence beta cell (β-cell) function and play a role in the progression to DM and what type of DM follows AP. Markers of DM types or β-cell function have not been studied post AP in pediatrics. Thus, this proposed study leverages our previous work in a novel design that allows for systematic generation of novel mechanistic data to define DM type, and the role of islet auto Abs and β-cell dysfunction as factors involved. The primary goal of this R03 are to investigate types of DM and extent of β-cell dysfunction from samples and subjects in prospective AP registry and biorepository at Cincinnati Children's Hospital Medical Center (CCHMC) generated under our NIDDK K23DK118190 designed to build predictive models for diabetes post AP. The primary objective of this project is to improve understanding of post AP DM, which will lead to improved patients' outcomes. This will be accomplished through our prospective longitudinal study design. Specific Aim 1 will define subtypes of DM and the temporal changes in relation to timing of Pre DM and DM post AP by testing for Type 1, Type 2 and Type 3c DM markers at different time points (3 and 12 months post AP). Specific Aim 2 will test the feasibility of conducting the standardized mixed meal tolerance testing (MMTT) in patients at 3 month and 12 month post AP, construct a model to define optimal samples collection time points needed for measuring β-cell responses to a stimulated test, and whether data points from stimulated testing provide value beyond simple fasting C peptide and glucose levels. The latter is important because MMTT is more cumbersome for pediatrics than a simple blood draw. We will also investigate the role of islet Ab positivity on β-cell function. Our proposal will help us better define progression to prediabetes then diabetes post AP to fill this knowledge gap. Successful completion of this study has the potential to lead to improved understanding of the mechanisms and risk factors for Pre-DM and DM, which will guide ultimately prevention and timely treatment of DM and its effect on children post AP.